The thalassemias are inherited disorders of globin chain synthesis in which molecular defects include deletion of structural genes, ineffective transcription of globin genes, synthesis of an abnormally unstable mRNA, and synthesis of a non-functional mRNA. Detailed molecular analysis of the physical arrangement of normal and thalassemic globin genes in cellular DNA should provide insights into the precise nature of these defects. The organization of globin sequences in cell DNA will be investigated by restriction endonuclease mapping techniques. The experiments proposed are designed to examine 1. the physical relationship of normal duplicated or genetically linked globin genes, 2. the fine structure of globin genes in normal DNA, and 3. the alterations in gene organization associated with specifc thalassemic syndromes. With respect to the thalassemias attention will focus on 1. the extent of structural globin gene deletion in alpha thalassemias, hereditary persistence of fetal hemoglobin syndromes, and delta-beta thalassemia and 2. the state of the beta globin gene in both beta degrees and beta ion thalassemias. Correlation of the molecular pathologies observed with the clinical features of specific thalassemic syndromes will ultimately provide a powerful approach to a more complete understanding of the pathogenesis of these disorders and the genetic elements vital to normal gene expression during erythropoiesis in man.